Mobilizing diversity: transposable element insertions in genetic variation and disease

In the 60 years since Barbara McClintock first discovered transposable elements (TEs), it has become increasingly recognized that these mobile sequences are important components of mammalian genomes and not merely 'junk DNA'. We now appreciate that these elements modify gene structure and alter gene expression. Through their mobilization, transposons reshuffle sequences, promote ectopic rearrangements and create novel genes. In rare cases, TE insertions which cause mutations and lead to diseases both in humans and in mice have also been documented. However, we are at the very earliest stages of understanding how mobile element insertions influence specific phenotypes and to the extent to which they contribute to genetic diversity and human disease.TEs are categorized into two major classes based on their distinct mechanisms of transposition. DNA transposons, referred to as Class II elements, mobilize by a 'cut-and-paste' mechanism in which the transposon is excised from a donor site before inserting into a new genomic location. These elements are relatively inactive in mammals, although one notable exception is a piggyBac element recently identified to be active in bats ([1], R Mitra and N Craig, personal communication). In humans, DNA transposons represent a small fraction (3%) of the genome [2]. Retrotransposons, also known as Class I elements, mobilize by a 'copy-and-paste' mechanism of transposition in which RNA intermediates are reverse transcribed and inserted into new genomic locations. These include long terminal repeat (LTR) elements such as endogenous retroviruses, and non-LTR retrotransposons. Endogenous retroviruses are remnants of viruses that have lost the ability to re-infect cells. These elements, which comprise 8% of the human genome, perform reverse transcription in cytoplasmic virus-like particles [2]. In contrast, non-LTR retrotransposons undergo a distinct mechanism of transposition whereby their RNA copies undergo reverse transcription and inte